The field of this invention is drug treatment, and relates particularly to the pulsed infusion of medications to treat cardiovascular disease and other cell, tissue, or organ disorders which necessitate treatment for an extended period of time. Treatment of cardiac disease may require long-term administration of drugs or other therapeutic agents to, for example, stimulate the heart muscle, keep vessels and passages clear of thrombi, or prevent organ rejection.
Current methods of drug administration for cardiac support have included the continuous infusion of a drug that is titrated to either a dose per body size or to a physiological end point, e.g., blood pressure. Both processes have been used in the administration of sympathomimetic drugs. However, it has been observed both in vivo and in vitro that with the continuous drug infusion there is tachyphylaxis to the drug, i.e., more drug is needed over time to achieve the same result. There is evidence in diverse biological systems that constant and increased doses of a specific agonist to a sympathetic receptor will result in desensitization, or the waning of the intensity of a response over time despite the continued presence of a stimulus of constant intensity (Benovic, J. L., et al., (1988) Ann. Rev. Cell Biol. 4:405-428; Lefkowitz, R. J., et al., (1980) Curr. Top. Cell. Regul. 17:205-230). Desensitization is a biochemical process that physically changes the receptor system molecule such that it is not able to respond to further administration of the therapeutic agent, thereby limiting the efficacy and duration of action. Densensitization of some receptor system molecules occurs when the molecule is phosphorylated.
Constant exposure of the receptor system molecule to the drug or other therapeutic agent may also result in down-regulation. (Lefkowitz, R. J., et al., (1980) Curr. Top. Cell. Regul. 17:205-230). Down-regulation occurs when there is a decrease in the number of receptor system molecules on the cell, thus decreasing the response to continued administration of the therapeutic agent.
An alternative method of drug administration known in the art is a bolus, or single, large dose of a medication administered at one time. Repeated bolus infusions of medications have been used to treat patients with terminal congestive heart failure (See, e.g., Baptista, R. J., et al., (1989) Ann. Pharmacol. 23:59-62) or with heart transplants (see, e.g., Miska, P. T., et al., (1988) J. Heart Transplant, 7(5):353-355).
However, depending on the amplitude (or magnitude) and duration of the bolus, down-regulation and/or desensitization may result. In cases where relatively high amplitude, long duration boluses are administered, there is often the same type of down-regulation and desensitization of molecules of the cell, tissue, or organ receptor system encountered with constant rate infusion of the drug or other therapeutic agent.
Thus, there is a need for an application technique that optimizes the effect of drug infusion, while minimizing the development and effects of resulting down-regulation and/or desensitization. Accordingly, it is an object of this invention to provide a method of pulsed application of a drug or other therapeutic agent that is at least as effective as a method of continuous administration. It is also an object of the invention to provide a method of drug administration which requires a lesser amount of drug or other therapeutic agent for the same response. An additional object is to provide a method of long-term administration of a drug or other therapeutic agent that minimizes the development and effects of down-regulation and/or desensitization of the target tissue to the administered agent.